This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. No new drugs against tuberculosis have been developed since the early 1960s. The emergence of multiple drug resistant strains and the long duration of current therapies (6 months) make the design of novel drugs crucial. The causative agent of tuberculosis, Mycobacterium tuberculosis (Mtb), produces two protein tyrosine phosphatases (PTPs), PtpA and PtpB. These PTPs are secreted into the host macrophage, where they subvert host immune functions. PTPs are emerging as a new and promising class of drug targets. The Mtb PTPs are particularly tractable targets because they can be targeted outside the Mtb cell coat that constitutes a highly impermeable barrier for small molecules. We have identified specific inhibitors of PtpA and PtpB with affinities in the low micromolar range. To guide the iterative improvement of these inhibitors, cocrystal structures of the PTPs with these inhibitors at the highest molecular resolution will be essential.